The broad, long-term objectives of this proposal are the development of novel methods for the parallel synthesis of quinacrine analogs and a thorough exploration of the structure-activity relationships of the acridines with respect to their ability to block the formation of PrP sc. The Specific Aims of this proposal are: 1) to explore the structure activity relationships of the A and C rings of the tricyclic heteroaromatic core of acridine, while allowing for synergy between the two rings, using a library of approximately 2000 acridine analogs to quinacrine; 2) to explore the structure activity relationships of the two pendant groups attached to the distal basic center of quinacrine, while allowing for synergy between the two sites, using a library of approximately 2000 analogs; 3) to develop new chemical approaches to the synthesis of alternate types of sidechains to the acridine ring system; 4) to explore the structure activity relationships of the linker between the acridine core and distal basic group functionalities of quinacrine, while allowing for some variation in the core heterocycle and the substitution of the distal basic group, using a library of approximately 2000 analogs; 5) to refine the structure activity relationships of quinacrine using a fully combinatorial library of approximately 2000 analogs variant in all three sub-portions of the drug. The members of this library will be targeted by information gained in all of the prior studies. Over the five year course of this project, we will build a library of 10,000 novel acridines for evaluation as potential therapeutics. The health relatedness of this project is that forms of quinacrine with increased efficacy and reduced toxicity might be quite useful in the treatment of prion diseases. The research design is the use of molecular design and combinatorial chemistry to develop PrP so inhibitors. The methods to be used are chemical synthesis, parallel synthesis, and quantitative structure activity relationship modeling.